N-phentlaliphatic-dihtoroxyphentnl



Patented Mar. 17, 1942 N-PHENYLALIPHATIC-DIHYDROXYPHENYL- ALIPHATICAIVHNES Fritz Kulz, Frankfort-on-the-Main, Germany, as-

signor to the firm Tropon-Werke Dinklage & Co., Cologne-Mulhelm, GermanyNo Drawing. Application August 9,1939, Serial No. 289,314. In GermanyAugust 16, 1938 Claims.

This invention relates to new aliphatic-aromatic amines of the generalformula (0H):CH1-R1lI IR:-C11H40H wherein R1 and R2 represent alkyl oralkylene radicles and Ra represents hydrogen or an alkyl or alkyleneradicle.

It is known that dihydroxyethylphenylamlne, like adrenalin, causesvaso-constriction and thereby an increase of the blood pressure bystimwherein R1 and R2 represent straight or branched alkyl or alkyleneradicals and R3 represents hydrogen or a straight or branched alkyl oralkylene radicle, possess analgesic properties if the followingconditions are satisfied:

(1 In addition to the two hydroxyl groups in one benzene ring there mustbe only one hydroxyl group in the other benzene ring.

(2) The sum of the carbon atoms present in R1 and R2 must be at least 6.

The positions of the two hydroxyl groups in the benzene rings areimmaterial, as is also their position with regard to each other. Theposition of the hydroxy group in the other benzene ring is as wellimmaterial.

R1 and R2 may be alkyl radicals with straight chains such as methyl,ethyl, propyl, butyl, pentyl, hexyl or alkyl radicals with branchedchains such as isobutyl,,isopentyl or tertiary pentyl, or alkyleneradicals with straight chains such as propenyl, butenyl, pentenyl,hexenyl, or alkylene radicals with branched chains such as isobutenyl orbranched pentenyls or hexenyls. The carbon atoms present in R1 and R2may be divided between R1 and R: as desired. Their total number howevermust be at least four and should preferably not exceed ten. Theanalgesic properties of these new compounds are, as has been found,within these limits the greater, the greater is the total number ofcarbon atoms contained in R1 and R2.

B: may represent hydrogen or an alkyl or alkylene radical. Preferably Radoes not contain more than four carbon atoms.

Besides the two hydroxyl groups in one benzene ring and one furtherhydroxyl group in the other benzene ring, the two benzene rings maycontain other substituents, such as hydrocarbon residues, for examplestraight or branched alkyl or alkylene radicals or alkoxy or alkylenedioxy radicals, whereby the analgesic properties in relation to theother properties can be influenced to a manifold degree.

The production of the new compounds can be eflected by introducinga-phenylalkyl or phenylalkylene radical into a primary or secondarymonophenylalkylamine or monophenylalkyleneamine, the benzene ring of oneof these two components having present therein two hydroxyl groups andthe benzene ring of the other component having therein one more hydroxylgroup.

Another way of producing these newcompounds consists in converting thecorresponding compounds in which at least one of the hydroxyl groups isesterified or etherified in known manner into compounds with freehydroxyl groups. The opening of the etherified or esterified hydroxylgroups can be efiected in known manner, for example by heating theinitial materials with dilute or concentrated mineral acids, such ashydrobromic acid or hydriodic acid or with aluminium halides, such asaluminium chloride or aluminium bromide or-with phosphorus pentachlorideor phosphorus pentabromide or in particular in the cases in whichalkylene dihydroxy groups are present by heating with a mineral acid,such as hydrochloric acid or hydrobromic acid in the presence ofsubstances which react easily with formaldehyde, such as phloroglycineor resorcinol.

The production of these initial materials with etherified or esterifiedhydroxyl groups which are to be split oil can be eiiected according toknown methods for the production of secondary or tertiary amines, forexample by condensing aldehydes or ketones with amines and hydrogenatingthe Schiffs bases formed or by heating an amine and an aldehydeaccording to the Leuckart-Wallach process in the presence of formic acidor other easily oxidisable substances or by reacting togethermonophenyialkylamines or monophenylalkyleneamines with a phenylalkylhalide or a phenylalkylene halide, two hydroxyl groups being containedin the benzene ring of one of the two components, and one more hydroxylgroup being contained in the benzene ring of the other component, ofwhich three hydroxyl groups at I least one is etherified or esterified.

EXAMPLES 1. Production of a-methyl-e-SA-dihydroxyphenylethyl-d-methyl-'y' 4' -hydroxyphenylpropylamine CH: CH;

| no CHrGE-III-ClF-Clh-CH I n no C H N Calculated 57,55 6,61 3,53 Found57,75 6,75 3,40

2. Production of (a-methyZ-p-3,4-diomyphenylethyl) (y-4'-o:cy-phenyl-propyl) amine C' l IIOfl-CHiCH-I? CHPCH2CHV (W H l uo-V Von 3.0 gms. of(a-methyl-e-3,4-dimethoxyphenylethyl) ('y 4 methoxyphenyl propyl) amine(produced by catalytic hydrogenation of the Schiffs base froma-methyi-p-3A-dimethoxyphenylethylamine and-y-4'-methoxyphenyl,-propylaldehyde) are heated with 50 com. of48-bercent hydrobromic acid for two hours in a stream of carbon dioxide.Then the hydrobromic acid is distilled off in the vacuum and the residueabsorbed in 15 com. of water is, if desired, decolorated with animalcharcoal. By adding hydrobromic acid the(a-methyl-54,4-dioxy-phenylethyl) 4' oxyphenyl-propyl)amine-hydrobromide is crystallised out.

3. Production of (a-methyl-p-3,4-dio.ryphenylethyl)(a-methyl-p-t'-oxyphenylethyl) -amine cm cm 4.0 gms. of(a-methyl-fl-3A-dimethoxyphenylethyl) a methyl- 5 4 -methoxyphenylethyl)amine-hydrochloride are heated with 50 com. constant boiling hydrobromicacid for two hours in a stream of carbon dioxide under reflux.Thereafter about of the hydrobromic acid are distilled off in a vacuum.When cooling down slowly the hydrobromide of the (a-methyI-B-BA-dioxyphenylethyl) (oz methyl e4- oxyphenylethyl) -amines precipitates.

What I claim is:

1. An aliphatic-aromatic amine of the formula wherein R1 and R2 arehydrocarbon radicals selected from the group consisting of alkylene andunsaturated alkylene radicals, the total number of carbon atoms in suchradicals being at least s x 2. a-methyl- ,33,4-dihydroxy-phenylethyl-amethyl- -4'-hydroxyphenyl-propyl-amine.

3. (a-methyl-p-BA-dihydroxymhenylethyl) 4-hydroxy-phenylpropyl) -amine.

4. (a-methyl-p-3,4-dihydroxy-phenylethyl) (amethyl-p4'-hydroxy-phenyl2-amine.

5. An aliphatic-aromatic amine of the formula Rq-ITI-Rl I H -ou whereinR1 and R2 are hydrocarbon radicals selected from the group consisting ofalkylene and unsaturated alkylene radicals, the total number of carbonatoms in such radicals being six to ten.

FRITZ KULZ.

